Geranylgeranyltransferase I promotes human glioma cell growth through Rac1 membrane association and activation.

Abstract

Geranylgeranyltransferase I (GGTase-I) is responsible for the posttranslational lipidation of several signaling proteins such as RhoA, Rac1, and Cdc42, which contribute to tumor development and metastasis. However, the role of GGTase-I in the progression of human glioma is largely unknown. Here, we provide the evidence that Rac1 mediates the effects of GGTase-I on the proliferation and apoptosis in human glioma cells. We found that GGTase-I was abundantly expressed in human primary glioma tissues. Inhibition or downregulation of GGTase-I markedly decreased the proliferation of glioma cells and induced their apoptosis, while overexpression of GGTase-I promoted cell growth in vitro. Inactivation of GGTase-I eliminated geranylgeranylation of RhoA and Rac1, prevented them from targeting to the plasma membrane, and inhibited Rac1 activity. Furthermore, overexpressing wild type or constitutively active Rac1 stimulated glioma cell growth, similar to the effect of GGTase-I overexpression. Importantly, overexpressing dominant-negative Rac1 or Rac1 with the prenylation site deleted or mutated abrogated GGTase-I-induced proliferation in glioma cells. These results confirm the view that geranylgeranylation is essential to the activity and localization of Rho family proteins and suggest that Rac1 is required for GGTase-I-mediated glioma growth.

• Authors: Xiuping Zhou, Jinming Qian, Lei Hua, Qiong Shi, Zhi Liu, Yinfu Xu, Ben Sang, Jianbing Mo, Rutong Yu
• Journal: Journal of molecular neuroscience : MN (J Mol Neurosci) Vol. 49 Issue 1 Pg. 130-9 (Jan 2013) ISSN: 1559-1166 [Electronic] United States
• PMID: 23073905 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• RAC1 protein, human
• RNA, Small Interfering
• Alkyl and Aryl Transferases
• geranylgeranyltransferase type-I
• rac1 GTP-Binding Protein
• rhoA GTP-Binding Protein

Topics

• Alkyl and Aryl Transferases (genetics, metabolism)
• Apoptosis
• Brain Neoplasms (enzymology, pathology)
• Cell Line, Tumor
• Cell Membrane (metabolism)
• Cell Proliferation
• Gene Deletion
• Glioma (enzymology, pathology)
• Humans
• Mutation
• Prenylation
• Protein Transport
• RNA, Small Interfering
• rac1 GTP-Binding Protein (genetics, metabolism)
• rhoA GTP-Binding Protein (metabolism)